PHARMACOKINETICS OF IN-111-LABELED ANTI-P97 MONOCLONAL-ANTIBODY IN PATIENTS WITH METASTATIC MALIGNANT-MELANOMA

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  • 1 January 1985
    • journal article
    • research article
    • Vol. 45  (5) , 2382-2386
Abstract
Patients (28) with metastatic malignant melanoma received anti-p97 murine monoclonal antibody (96.5) infused over 2 h at doses between 1 and 20 mg coupled to either 2.5 or 5.0 mCi of 111In by the bifunctional chelating agent diethyltriaminepentaacetic acid. Clearance of 111In from plasma closely fit an open, 1-compartment mathematical model (r2 > 0.90). The overall half-life of 111In in plasma was .apprx. 31 h and did not appear to be dependent on the total dose of antibody administered. The apparent volume of distribution of the 111In-label approximated the total blood volume (7.8 .+-. 0.7 l) at the 1-mg dose and decreased to 3.0 .+-. 0.14 l at the 20-mg dose, suggesting saturation of antigenic or other extravascular binding sites at higher antibody doses. The clearance of the murine monoclonal antibody itself from plasma was measured by an enzyme-linked immunosorbent assay. The pharmacokinetics for the murine antibody in plasma also fit an open, 1-compartment mathematical model. All pharmacokinetic parameters for unlabeled antibody closely paralleled those found for 111In-labeled antibody pharmacokinetics. This suggests that the 111In radiolabel remains complexed to the monoclonal antibody after in vivo administration. The cumulative urinary excretion of the 111In label over 48 h was between 12 and 23% of the total administered dose and was assumed to represent 111I-labeled chelate complex unattached to antibody. Analysis of the 111In label in spleen, liver, heart and kidney showed that the concentration of label in liver tissue was reduced with increasing antibody doses and coincided with changes in the apparent volume of distribution. Thus murine monoclonal antibodies are cleared slowly from the circulation in humans''; early, rapid distribution of labeled antibody to the liver can be reduced by increasing the dose of unlabeled antibody. This may be particularly important in limiting hepatic toxicity when administering antibody coupled to drugs, radionuclides, or toxins.